Infection with human papillomaviruses (HPV) is strongly associated with the development of cervical and anogenital cancers, which are frequently found in HIV-infected individuals. Specific and effective therapies for HPV infection are not available. A HPV vaccine, if successful, will not be effective in immunosuppressed individuals. Our long-term goal is to develop therapeutic strategies for elimination of HPV infection and HPV-induced cancers in people with AIDS. The HPV E6 and E7 proteins are essential for viral replication and HPV-induced cellular transformation. E6 inhibits E7-induced apoptosis. E6 performs its functions through interaction with the tumor suppressor p53 and other cellular proteins. We plan to target E6 for inhibition. To achieve this goal, we have identified an E6 binding motif that is conserved among several E6-binding proteins. We have determined the structure of peptides containing this motif and identified amino acids that are important for E6 binding. These amino acids and the structure of the E6-binding domain defined a pharmacophore-the spatial distribution of the atoms needed to bind E6. We hypothesize that small molecules presenting the pharmacophore will bind E6 and block its interaction with cellular proteins and thus induce apoptosis. We have selected a set of compounds for presence of the pharmacophore and identified several compounds that specifically inhibited E6 activities with modest potency in vitro. In this proposal, we will (1) synthesize chemical libraries based on the pharmacophore and the active compounds and screen the library for compounds that bind E6 using our newly developed encoding combinatorial chemical synthesis technology; and (2) test the specificity and potency of the hits obtained from chemical optimization. We expect to identify compounds that specifically inhibit E6 functions with greatly improved potency. These studies will lead to the development of drugs to treat HPV infection and HPV-associated cancers in HIV-infected patients.